Myeloma bone and extra-medullary disease: Role of PET/CT and other whole-body imaging techniques

Critical Reviews in Oncology/Hematology 101 (2016) 169–183

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Myeloma bone and extra-medullary disease: Role of PET/CT and other whole-body imaging techniques Giuseppe Rubini a , Artor Niccoli-Asabella a,∗ , Cristina Ferrari a , Vito Racanelli b , Nicola Maggialetti c , Francesco Dammacco b a

Nuclear Medicine Unit, University of Bari Medical School, Bari, Italy Department of Internal Medicine and Clinical Oncology, Guido Baccelli Unit, University of Bari Medical School, Bari, Italy c Department of Medicine and Health Science, Radiodiagnostic Section, University of Molise, Campobasso, Italy b

Contents 1. 2. 3.

4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 Pathogenesis of MM-related bone disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 Imaging features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 3.1. Technical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 3.2. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 3.2.1. Imaging in the diagnosis and staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 3.2.2. Imaging of response to treatment and disease progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 Usefulness of imaging: what and when? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 Imaging of the future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

a r t i c l e

i n f o

Article history: Received 16 December 2014 Received in revised form 8 February 2016 Accepted 3 March 2016 Keywords: Bone disease Diffusion weighted whole body imaging with background body signal suppression (DWIBS) Multiple myeloma Positron emission tomography/computed tomography (PET/CT) Positron emission tomography/magnetic resonance (PET/MR) Whole body magnetic resonance (WB-MR)

a b s t r a c t Multiple myeloma (MM) is the second most common hematological malignancy. Although it can affect different organs, the bone compartment stands out both in terms of prevalence and clinical impact. Despite the striking advances in MM therapy, bone disease can remarkably affect the patient’s quality of life. The occurrence and extension of bone marrow and extra-medullary involvement should be carefully assessed to confirm the diagnosis, to locate and whenever possible prevent dreadful complications such as pathological fractures and spinal cord compression, and to establish suitable therapeutic measures. Many imaging techniques have been proposed for the detection of MM skeletal involvement. With the development of more sophisticated imaging tools, it is time to use the right technique at the right time. Based on the review of the literature and our own experience, this article discusses advantages and disadvantages of the different imaging methods in the work-up of MM patients, with particular emphasis on the role that PET/CT can play. It is emphasized that whole body low-dose computed tomography should be the preferred imaging technique at baseline. However, bone marrow infiltration and extramedullary manifestations are better detected by whole body magnetic resonance imaging. Positron emission tomography/computed tomography, on the other hand, combines the benefits of the two

Abbreviations: [11C]CHO, [11C]Choline; [11C]MET, [11C]Methionine; [18F]FDG-PET/CT, 2-deoxy-2-[18F]fluoro-d-glucose-positron emission tomography/computed tomography; [18F]FLT, 3 -[18F]fluoro-3 -deoxy-l-thymidine; [18F]NaF, [18F]sodium-fluoride; [99mTc]MDP, [99mtechnetium]methylene-diphosphonate; [99mTc]sestaMIBI, 2-methoxy-isobutyl-isonitrile[99mTc]technetium; ASCT, autologous hematopoietic stem cell transplantation; BS, bone scintigraphy; CRAB, hypercalcemia, renal involvement, anemia, lytic bone lesions; FoV, field of view; GLUT, glucose transporter; IMWG, International Myeloma Working Group; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MRD, minimal residual disease; MTV, metabolic tumor volume; OS, overall survival; PFS, progression free survival; PPV, positive predictive value; SBP, solitary bone plasmacytoma; SMM, smoldering multiple myeloma; STIR, short time inversion recovery; SUVmax, maximum standardized uptake value; T1w, T1-weighted; T2w, T2-weighted; TLG, total lesion glycolysis; TTP, time to progression; WB-LDCT, whole body low dose computed tomography; WB-MDCT, whole body multidetector computed tomography; WB-MR, whole body magnetic resonance; WB-MR/DWIBS, WB-MR/diffusion-weighted imaging with background body signal suppression; WB-XR, whole body skeletal X-ray. ∗ Corresponding authors at: Piazza G. Cesare, 11, Bari 70124, Italy. E-mail address: [email protected] (A. Niccoli-Asabella). http://dx.doi.org/10.1016/j.critrevonc.2016.03.006 1040-8428/© 2016 Elsevier Ireland Ltd. All rights reserved.

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mentioned imaging procedures and is particularly useful not only for the detection of osteolytic lesions unrevealed by conventional X-ray, but also in the assessment of prognosis and therapeutic response. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

2. Pathogenesis of MM-related bone disease

Bone involvement is the most frequent feature of Multiple Myeloma (MM), occurring in approximately two-thirds of patients at diagnosis and in virtually all patients during the course of disease. It remarkably affects the patient’s quality of life and is a major cause of morbidity and mortality (Kyle et al., 2003; Terpos and Dimopoulos, 2005). At the present time, guidelines for initiation of anti-myeloma therapy were based on criteria designated with the acronym CRAB that include hyper-Calcemia, Renal involvement, Anemia, and lytic Bone lesions detected by a skeletal survey. However, the IMWG has recently stated that CRAB features need to be implemented taking into account substantial changes in terms of laboratory testing and imaging methods for the diagnosis of MM in the last years (Rajkumar et al., 2014). Validated biomarkers such as clonal bone marrow plasma cells of 60% or greater, involved/uninvolved serum free light chain ratio of 100 or greater, and Magnetic Resonance (MR) with more than one focal lesion destruction (≥5 mm in size) can be considered as useful criteria for the definition of MM. Bone lesions seen on Computed Tomography (CT), including whole-body low-dose CT (WB-LDCT) or Positron-Emission Tomography/Computed Tomography (PET/CT) should also be regarded as fulfilling the CRAB requirement, whether or not such lesions can be detected on skeletal radiography. Obviously, a delay in undertaking a correct diagnosis of MM and the consequent delayed commencement of therapy could be of detriment to the patient (Dimopoulos et al., 2015). Assessment of bone destruction is no doubt essential, but it actually describes a secondary event of an advanced disease initially arising in the bone marrow. Consequently, bone imaging is of crucial importance for diagnosis and staging of overt MM that requires treatment, as well as for its differentiation from Monoclonal Gammopathy of Undetermined Significance (MGUS) and from Smoldering Multiple Myeloma (SMM). Although conventional skeletal survey has been considered for many years the gold standard to detect or rule out bone disease in patients with plasma cell malignancies, more advanced and sensitive cross-sectional imaging techniques are now under extensive evaluation. Such techniques include WB-LDCT, whole-body MR (WB-MR) and 2-deoxy-2-[18F]fluoro-d-glucose PET/CT ([18F]FDGPET/CT). With the advent, development and spread of these novel imaging techniques, it has become possible to pursue the morphological and functional characterization of organs and tissues involved by a large variety of disease conditions. The same imaging procedures are also being used with increasing frequency in patients with monoclonal plasma cell disorders, with the aim of achieving information on disease distribution (bone marrow, bone and extra-medullary disease), disease activity and minimal residual disease after therapy. However, the data of the literature are mostly incomplete and heterogeneous. In the present review we have tried to provide a comprehensive examination of advantages and disadvantages, limits and opportunities of PET/CT and other whole-body imaging techniques, in the study of myeloma bone disease with the aim of performing the right imaging technique for the right patient at the right time.

Bone disease, most frequently of the osteolytic type, occurs in approximately 70–80% of MM patients. In addition, a systemic bone loss can be observed, leading to diffuse osteopenia or even to severe osteoporosis, enhanced by the almost invariable use of high-dose glucocorticoids. However, at variance from the mechanism(s) underlying the formation of lytic bone metastases in other cancer patients, the basic pathophysiologic abnormality of the bone destructive process in MM is the increased osteoclastic bone resorption and conversely the reduced differentiation from precursors to mature osteoblasts, with consequent bone loss and inhibition of new bone formation (Roodman, 2009). How does the mentioned imbalance occur? A detailed description of the complex interactions between malignant plasma cells and bone marrow is beyond the aims of the present paper. Shortly, proliferating myeloma cells, through their adhesion to hematopoietic cells, are able to stimulate the production of cytokines and growth factors by these cells and their release in the bone marrow microenvironment. Myeloma cells participate in the cytokine secretion by the establishment of autocrine and paracrine loops. In addition, plasma cell adhesion to stromal cells may result in the up-regulation of angiogenic factors that stimulate angiogenesis and augment the microvascular density of the bone marrow. Myeloma cells can also adhere to extracellular matrix proteins and this may result in the up-regulation of cell cycle regulatory proteins and anti-apoptotic proteins (Palumbo and Anderson, 2011). This synthetically exposed pathogenetic pathway accounts for the therapeutic efficacy of the second-generation anti-MM drugs. Among proteasome inhibitors, first-in-class bortezomib is widely employed in the treatment of MM. In addition to stimulating apoptosis and down-regulating angiogenesis, bortezomib has been shown to act on bone metabolism in preclinical and clinical studies. It can in fact stimulate osteoblast growth and differentiation, and it can also inhibit osteoclast development and activity (Mohty et al., 2014). On the other hand, immunomodulatory drugs, such as lenalidomide, can also enhance apoptosis and inhibit angiogenesis, cell adhesion, and cytokine circuits (Palumbo and Anderson, 2011). Bone pain, high risk of pathological fractures, spinal cord compression or, in general, skeletal-related events are common clinical features in MM (Tosi, 2013). Spine is most frequently affected, although MM-related lesions can affect bones with variable frequency: vertebrae (66%), ribs (45%), skull and shoulders (40%), sternum and pelvis (30%), and long bones (25%) (Healy et al., 2011). Spine is also the site where a Solitary Bone Plasmacytoma (SBP) can develop with the highest frequency. A study of 206 patients affected with SBP showed an average incidence of 50% for the spine, 12% for the pelvis, 9% for ribs, 8% for upper extremities, 6% for maxillary bone, 5% for the skull, 5% for lower extremities and 5% for the sternum (Knobel et al., 2006). Thoracic and lumbar spines are more frequently affected while cervical spine is seldom involved (Tosi, 2013). There is a clear association between the extent of disease (in terms of the number of lytic lesions) and tumor load at diagnosis, as reported in the Durie and Salmon (1975) staging system. Moreover, according to the updated IMWG criteria (Rajkumar et al., 2014), the detection by CT, or WB-LDCT or PET/CT (increased uptake on PET plus evidence of underlying osteolytic bone destruction on the CT

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portion of the examination) of one or more osteolytic bone lesions ≥5 mm in size should be considered as a criterion for bone disease in MM, thus meeting the CRAB requirement, whether or not such lesions are detectable on skeletal X-ray. On the other hand, at least two focal lesions (≥5 mm in size) should be detected by MR to start treatment in patients with high risk SMM: this finding should in fact be considered a significant predictor of progression.

3. Imaging features The ideal imaging technique for MM patients should be able to achieve a whole body evaluation, recognize both osteolytic lesions and bone marrow infiltration, reveal foci of extra-medullary disease, detect and predict skeletal complications, evaluate treatment response, allow a risk stratification, and be endowed with a reasonable acquisition time, low radiation exposure, low cost, good patient’s compliance, no contraindications, and a wide availability in the territory. A suitable balance of the major clinical information achievable with the best technical performance should also be required.

3.1. Technical features As already mentioned, whole body skeletal X-Ray (WB-XR) has long been regarded as the reference standard imaging modality for the detection of MM-related bone disease (Dimopoulos et al., 2015, 1993, 2011; D’Sa et al., 2007). A complete skeletal survey should include ten to twenty radiographs of the skeleton: frontal and lateral views of chest, skull, humeri, femora, pelvis and the whole spine must be performed and additional projections may also be necessary. This methodology is time-consuming and the various positions required can be painful for patients who are often elderly and disabled due to previous pathological fractures. Image quality is highly dependent on patient positioning and needs a cooperative patient and an experienced technician (Healy et al., 2011). WB-XR, on the other hand, has the advantage of being widely available, relatively inexpensive and allows large areas of the skeleton to be visualized with low radiation exposure (0.1–1.5 mSv for radiograph). However, some areas such as the sternum, ribs, scapulae and the spine are difficult to be accurately evaluated with plain XR due to superimposed images of organs and/or skeletal segments, or undetectable because they are outside the Field of View (FoV) of the technique (Zamagni and Cavo, 2012). Over the past few years, whole body multidetector CT (WBMDCT) has been explored as an alternative to WB-XR, based on its high sensitivity and resolution imaging of cortical and trabecular bone, fast imaging acquisition time and high-quality 3D reconstruction (Mahnken et al., 2002; Furtado et al., 2005). However, its major disadvantage is the high level of radiation exposure (>35 mSv) (Lütje et al., 2009; Gleeson et al., 2009). Furthermore, caution is needed in the use of intravenous iodine-containing contrast agents for the potential risk on renal function in patients with urinary excretion of monoclonal light chains. In order to overcome these limitations, WB-LDCT protocols have been investigated (Horger et al., 2005, 2007; Kröpil et al., 2008). Due to the high intrinsic bone contrast, the tube current can be significantly lowered (i.e. 50–100 mA, depending on the weight of the patient), resulting in an effective equivalent dose similar to that of a WB-XR (4–7.5 mSv) (Hillengass and Landgren, 2013). WB-LDCT has also the practical advantages of being rapid and with the patient lying comfortably; furthermore, iodine-containing contrast agents are not required, making it an even more attractive screening option (Healy et al., 2011). The interest in the use of this technique as an alternative to standard radiography is increasing, so that the IMWG has

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suggested since 2011 that this tool should replace WB-XR in the clinical practice (Dimopoulos et al., 2011). Due to its ability to visualize large volumes of bone marrow without inducing radiation exposure, MR has become a favored imaging method to assess marrow involvement. Multiple sequences have been proposed to identify focal or diffuse bone marrow implication: T1-weighted (T1w), T2-weighted (T2w), and Short Time Inversion Recovery (STIR) are the most sensitive sequences for depicting MM-alterations (Weininger et al., 2009). The use of contrast-enhanced imaging requires repeating scanning during and after intravenous infusion of a gadolinium-containing contrast agent, using fast T1w sequences (Healy et al., 2011). The main limitation of MR is the prolonged acquisition time, requiring about 40 min. Other disadvantages are high costs, limiting patient factors (such as claustrophobia or metal devices in the body) and particularly the restricted FoV (Lütje et al., 2009). With the recent advances in MR technology, such as the moving table, the use of multicoil elements and the improvement in image processing, this technique has become sufficiently fast and diagnostically reliable for whole-body study. WB-MR is based on T1w and WB-STIR sequences that have gained wide acceptance in detecting occult malignant disease in the skeleton (Kavanagh et al., 2003). Usually, WB-MR does not require contrast infusion and the total scan time for a whole-body image is reduced to about 30 min. Given that WB-MR is not yet widely employed and few studies have been designed to compare this procedure with other techniques (Zamagni and Cavo, 2012), the clinical experience of this imaging modality as a screening tool in MM patients is yet to be clearly established. The advent of PET scanners has changed the approach to the assessment of MM patients from morphologic to functional point of view. PET is a non-invasive functional imaging technique that routinely uses [18F]FDG, a glucose analogue labeled with a positron emitter that detects tumors based on their glucose demand. The intracellular [18F]FDG uptake is related to the glucose transport (GLUTs) molecules expressed on the cell membrane and to the glycolytic activity (Caldarella et al., 2012; Niccoli-Asabella et al., 2013). The use of [18F]FDG-PET in MM results in numerous advantages. First of all, it performs a whole body scan in a reasonable time. In addition, it is a single procedure capable of detecting both bone marrow involvement and extra-medullary lesions with high sensitivity and specificity (Bredella et al., 2005). The advent of hybrid PET/CT scanners has offered the possibility to achieve both metabolic and morphological information: while [18F]FDGPET detects areas with intense hypermetabolic activity (active lesions), CT scan can visualize lytic lesions with a resolution limit of 0.5 cm (Zamagni and Cavo, 2012). The [18F]FDG-PET/CT scan takes 20–25 min to perform. Furthermore, a low dose of radiopharmaceutical is injected into the patient, who is scanned by a multidetector tomographic system, usually with a LDCT component, to minimize radiation exposure. [18F]FDG-PET/CT scan exposes patients to approximately 13 mSv (6 mSv for a 370 MBq [18F]FDG dose from the PET scan and 7 mSv from the LDCT) (Mena et al., 2011). Protocols to further minimize doses and the corresponding radiation for the patient are in progress. The technical features of each imaging method are summarized in Table 1. 3.2. Clinical features 3.2.1. Imaging in the diagnosis and staging The aim of imaging in baseline MM evaluation is to detect or rule out bony lesions, in addition to extra-medullary involvement, in order to discriminate MM from its precursor states and avoid unnecessary treatment. In addition, it has the role of highlighting and correctly staging patients with overt bone disease in order to

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Table 1 Main technical characteristics of different whole body imaging techniques. Imaging

Main technical features

Technique

radiation exposure

whole body exploration

exam acquisition time

patient positioning

limitations

costs

WB-XR

2–4 mSv

10–20 radiographs

30–45 min

none

lowest

WB-LDCT

4–7.5 mSv

yes

10 min

various positions required (can be painful for patients, often elderly and with pathological fractures) comfortable

none (contrast agent not required)

WB-MR

no

yes

30 min

WB-FDG PET/CT

12–14 mSv

yes

20 min

4.2 in half of the positive cases. It is interesting to emphasize that, while a conventionally defined CR was shown in 53% of the patients following treatment, PET/CT was negative in 70% of the patients, and these negative findings were shown to be an independent predictor of prolonged PFS and OS. In addition, 12% of the patients with persistent SUVmax > 4.2 following first-line therapy experienced skeletal progression that could be revealed only by PET/CT. Thus, the results of this retrospective study indicate that a suitable application of this technique may result in a more precise and reliable assessment of CR and,

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Table 2 Comparison of different whole body imaging techniques with regard to the clinical features. Imaging

Clinical features

Technique

osteolytic lesions

bone marrow infiltration

extra-medullary disease

skeletal complications

prognostic value

treatment response

WB-XR

– low sensitivity (in early disease stage); false-negative (lesions overlapped or outside the radiograph FOV) – low specificity (in distinguishing myelomarelated osteoporosis)

not assessable

not assessable

not assessable

not assessable

not assessable (no evidence of lytic bone lesions healing)

WB-LDCT

high sensitivity

low sensitivity to detect diffuse or focal bone marrow involvement

low sensitivity (technical setting used to optimize the osseous structure assessment)

high accuracy to detect fractures or osseous instability

not assessable

not assessable (no evidence of lytic bone lesions healing)

WB-MR

– high sensitivity (early stage of disease) – high specificity (in distinguishing myelomarelated osteoporosis)

high accuracy to detect diffuse and focal bone marrow involvement

high accuracy to detect soft tissue masses

– high accuracy to predict and detect pathological fractures or osseous instability – high accuracy to detect spinal cord or nerve compression

high correlation between MR bone marrow pattern and prognosis

delayed evaluation (slight changes in the early post-treatment phase)

WB-FDG PET/CT

– high sensitivity (accurate detection of metabolic changes even in early disease stage) – semiquantitative evaluation (SUV) – morphologic information (osteolytic lesion > 0.5 mm)

– high accuracy to detect focal bone marrow involvement: – moderate sensitivity to detect diffuse infiltration

high accuracy to detect soft tissue masses

low specificity (improved by morphologic information)

high correlation between number of focal lesions and prognosis

– high reliability metabolic information (even in the early post-treatment phase) – high NPV that correlate with CR or low risk of PD)

conversely, in the recognition that certain patients can develop a skeleton-restricted progression. The most remarkable results have been described in the prospective studies of the Little Rock and Bologna groups in newly diagnosed MM patients treated with bortezomib-based induction therapy and Autologous Stem Cell Transplantation (ASCT) respectively. In these studies, persistent [18F]FDG uptake after treatment was strongly associated with a worse Progression Free Survival (PFS) and Overall Survival (OS), both for the 239 patients treated with “total therapy 3” program (Barlogie et al., 2007) and for the 192 patients treated with novel agent-based induction and ASCT (Nanni et al., 2013). [18F]FDG uptake decreases rapidly after effective therapy, while persistent [18F]FDG-PET/CT positivity correlates with early relapse (Durie, 2006). More recently, the Little Rock group (Usmani et al., 2013) reported the prognostic value of early PET/CT performed on day 7 of the induction treatment: a 3-year OS and PFS were observed in 63% and 56% respectively of the patients presenting with more

than 3 focal lesions compared with 78% and 82% of the patients with 1–3 focal lesions. [18F]FDG-PET/CT is therefore considered a reliable predictor of prognosis and its serial use after induction treatment and subsequent ASCT could contribute to the design of individualized therapies (Patriarca et al., 2015). The information on the odds of relapse after MM lesions become undetectable by PET/CT is still limited. However, the following observation may be enlightening in this context. In a study enrolling 37 patients with serologically proven relapse from MM (Lapa et al., 2014), 28 (76%) had a positive [18F]FDG-PET/CT scan with intra-medullary, extra-medullary or both types of lesions. Among extra-medullary lesions, lymph node involvement was most commonly seen (11/14: 79%), followed by soft tissues (6/14: 43%), liver (4/14: 29%), spleen (2/14: 14%) and lungs (2/14: 14%). In the same study, the [18F]FDG-PET/CT negativity turned out to be a favorable prognostic factor, given that in 14/37 (38%) patients with extra-medullary disease, Time To Progression (TTP) and OS were shorter than in the patients with no extra-medullary

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disease (median TTP 3.2 ± 3.4 months vs. 29.3 ± 0.0 months, p = 0.049; median OS 8.8 ± 1.5 months vs. not reached, p = 0.172). The number of intra-medullary lesions was also proved to be an important prognostic factor: median TTP was in fact 10.0 ± 6.8 months and median OS was not reached in patients with 1–10 lesions, whereas TTP was 4.1 ± 2.2 months and OS 7.0 ± 3.3 months (TTP p = 0.003; OS p = 0.023) in patients with more than 10 intra-medullary lesions (Lapa et al., 2014). Increasing therapeutic options and prolonged survival in MM have obviously raised interest in MRD, which now stands out as one of the most relevant prognostic factors in MM. Keeping in mind that plasma cell infiltration of the bone marrow may sometimes be patchy and that the extra-medullary involvement of MM is unusual but possible, both immunophenotypic and molecular assessments of MRD are a challenge in single bone marrow aspirates. These considerations emphasize the value of sensitive imaging techniques to redefine CR both at the intra-medullary (e.g., WB-MR and PET/CT) and extra-medullary levels (PET/CT). However, standardization of imaging techniques for the assessment of MRD and their comparison with other sensitive bone marrow-based methods (flow cytometry, polymerase-chain reaction, next-generation sequencing) are still lacking. On the other hand, the persistence of MRD remains an adverse prognostic feature, even for patients achieving a CR. Consequently, MRD monitoring by means of standardized, highly sensitive technique is essential if a tailored therapy of MM is to be pursued (Paiva et al., 2015). It has also been suggested that [18F]FDG-PET/CT can be useful in detecting therapy complications, such as inflammation or infection, which occur frequently in patients with severe immunosuppression and can lead to a change in the therapeutic strategy. It should, however, be emphasized that the activation of hematopoiesis after chemotherapy or the administration of hematopoietic growth factors (such as G-CSF and GM-CSF) can increase [18F]FDG uptake in the bone marrow (Mahfouz et al., 2005). One of the main limitations of serially used [18F]FDG-PET/CT is the heterogeneity of the visual criteria and the poor inter-observer reproducibility in the interpretation of the results. A rigorous standardization of the [18F]FDG-PET/CT protocol is required in order to achieve reproducible SUVs or consensus regarding imaging definitions and response criteria, as was done for solid tumors (Wahl et al., 2009). To the aim of standardizing the inter-observer reproducibility in the interpretation of [18F]FDG-PET/CT, Nanni et al. (2015) have established a score according to modified Deauville criteria which are applied in Hodgkin lymphoma and in certain types of non-Hodgkin lymphoma. The authors declare that these new visual criteria for interpreting FDG PET/CT imaging in MM patients are feasible and reliable in clinical practice. Clinical information that can be achieved from each imaging method is summarized in Table 2.

4. Usefulness of imaging: what and when? We have previously emphasized that the traditional skeletal survey for the diagnostic assessment of MM is affected with significant limitations compared with the more recent and sensitive imaging techniques. We have tried to summarize the main features of each imaging technique mentioned above, and have assigned a score related to the appropriateness of each technical/clinical feature (Table 3). Scores are directly derived from the scientific data synthetized in Tables 1 and 2, and their aim is an attempt to translate qualitative characteristics of each technical and clinical parameter into a quantitative assessment. As it can be inferred from Table 3, WB-XR has a high technical performance score but its clinical performance score is very low

Table 3 Three-points scale evaluation of technical and clinical features of whole-body techniques in multiple myeloma imaging. Point scale: 0–2 (0 = poorly suitable, 1 = averagely suitable, 2 = highly suitable). Imaging

WB-XR

WB-LDCT

WB-MR

WB FDG-PET/CT

A. Technical features 1. radiation exposure 2. whole body exploration 3. exam acquisition time 4. patient positioning 5. limitations 6. costs

1 1 1 1 2 2

1 2 2 2 1 1

2 2 0 1 1 0

0 2 1 2 1 0

8

9

6

6

1 0 0 0 0 0

2 0 1 1 0 0

2 2 2 2 2 1

2 2 2 1 2 2

Clinical performance score

1

4

11

11

overall performance score

9

13

17

17

Technical performance score B. Clinical features 7. osteolytic lesions 8. bone marrow infiltration 9. extra-medullary disease 10. skeletal complications 11. prognostic value 12. treatment response

because it can significantly underestimate bone disease both in the early phases of the disease and in the re-staging process. It is therefore important to address the question whether techniques more sensitive than WB-XR have to be routinely used to assess the extent of bone involvement in MM and whether the consequent increased costs and/or greater radiation exposure are justified by improved clinical outcome. As previously detailed, WB-LDCT should be preferred to WB-XR for shorter acquisition time, less discomfort for the patient and achievement of better information and, if available, clinicians have to take it into consideration. Nevertheless, neither WB-XR nor WB-LDCT is sufficient to properly stage and especially re-stage patients. MR is the most sensitive technique for assessing bone marrow involvement. In several studies MR, preferably WB, has been proven to be more sensitive than WB-XR and WB-LDCT for the detection of bone lesions and both focal or diffuse marrow involvement (BaurMelnyk et al., 2008; Walker et al., 2007; Ghanem et al., 2005). It has also been suggested as a tool in the initial evaluation of patients with MGUS. WB-MR has technical limitations but they are strongly overcome by the improvement of clinical performance that makes it one of the best imaging modalities in the management of MM, although more suitable in the staging phase than in post-therapy response assessment (Table 3). More recently, clinical research has assigned great interest in metabolic imaging. [18F]FDG-PET offers the possibility to visualize viable neoplastic tissue, both medullary and extra-medullary, with a single whole body scan. Furthermore, hybrid [18F]FDGPET/CT system allows to evaluate the presence of osteolytic lesions and accurately localize them, thus making it the gold standard technique in MM patients for staging and especially for the assessment of treatment response. However, [18F]FDG-PET/CT sensitivity resulted inferior to MR for spine evaluation, underestimating the disease in 30% of the patients, especially in the diffuse pattern involvement. For this reason, in case of negative [18F]FDG-PET/CT, a careful evaluation for MM bone disease should include MR of the spine in order to exclude the presence of a diffuse pattern infiltration, which could be poorly documented by [18F]FDG-PET/CT (Schirrmeister et al., 2002). The study by Shortt et al. (2009) is one of the few that directly compared [18F]FDG-PET/CT with WB-MR. They showed that WBMR assesses disease better than [18F]FDG-PET/CT with a higher sensitivity (68% versus 59%) and specificity (83% versus 75%). Other studies suggested that [18F]FDG-PET/CT is more accurate than MR

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Fig. 6. Current imaging algorithm for the diagnosis and staging of MM (Terpos et al., 2015). WB-LDCT (or WB-XR if WB-LDCT is not available) is the first-line imaging method, while [18F]FDG-PET/CT or WB-MR are applied as second-line techniques in selected conditions.

Fig. 7. Proposal of a more direct imaging algorithm for the diagnosis and staging of MM. The information achieved by the use of [18F]FDG-PET/CT plus spine MR or WB-MR at the first assessment of the patient may result in a shorter time to reach a final diagnosis.

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Table 4 Analysis of sensitivities, specificities, positive predictive values (PPV), negative predictive values (NPV) and diagnostic accuracy of each whole body imaging method, distinguishing between staging and treatment response evaluation. Method

exam’s reason

sensitivity

specificity

PPV

NPV

accuracy

reference study

study population

WB-XR WB-LDCT WB-MR 18F-FDG PET/CT WB-MR 18F-FDG PET/CT

Staging Staging Staging Staging treatment response treatment response

100% 100% 68% 59% 80.0% 50.0%

29.4% 55.6% 83% 75% 38.1% 85.7%

64.7% 88.2% 88% 81% 38.1% 62.5%

100% 100% 59% 50% 80.0% 78.3%

69.2% 89.7% / / 51.6% 74.2%

Gleeson et al. (2009) Gleeson et al. (2009) Shortt et al. (2009) Shortt et al. (2009) Derlin et al. (2013) Derlin et al. (2013)

39 pts 39 pts 24 pts 24 pts 31 pts 31 pts

for detecting extra-medullary disease, especially where WB-MR imaging is not performed (Fonti et al., 2008). The combined use of [18F]FDG-PET/CT and WB-MR allows to detect sites of active MM with a sensitivity of 92% and a positive predictive value of 100% (Healy et al., 2011; Zamagni et al., 2007). The multiple and important clinical information achievable by a [18F]FDG-PET/CT examination in MM largely overcomes technical limitations. WB-MR and [18F]FDG-PET/CT have also emerged as promising tools to measure and monitor Minimal Residual Disease (MRD), especially in extra-medullary MRD. A dependable assessment of MRD would in fact contribute to a better monitoring of treatment efficacy and to the avoidance of over- and under-treatment, especially when planning consolidation or maintenance treatments (Paiva et al., 2015) (Table 4). As it appears from Table 1, to date none of the morphological or functional imaging techniques are able to satisfy all the requirements. A consensus and standardized imaging protocol is still lacking both for staging patients with newly diagnosed MM and for re-staging those followed-up in the course of treatment or for disease progression. However, [18F]FDG-PET/CT and WB-MR represent the best diagnostic tools to evaluate MM patients with equally high overall performance score (Table 3), in that both techniques are able to properly stage and monitor therapy response. As recently reported by the European Myeloma Network (Terpos et al., 2015), the algorithm for imaging in MM is focused on WBLDCT (or WB-XR if WB-LDCT is not available), considering WB-MR and especially [18F]FDG-PET/CT as second-line techniques in clinically selected subsets of patients (Fig. 6). However, the use of [18F]FDG-PET/CT and WB-MR as first-line imaging approach could result in the achievement of all clinical information required to perform a correct diagnosis and establish an appropriate and early treatment (Fig. 7). Additional advantages include assessment of response to therapy and re-staging. 5. Imaging of the future New imaging techniques with increased accuracy are under investigation to correctly stage and evaluate treatment response, and above all for the early detection of MM. WB-MR integrated with diffusion-weighted imaging with background body signal suppression (WB-MR/DWIBS) is an emerging and promising technique to evaluate oncologic and non-oncologic lesions. DWIBS sequence reflects the random extra-, intra- and trans-cellular motion of water molecules in biological tissues, highlighting an impeded (low) diffusion, which results in a high signal intensity in different pathological conditions (e.g., an increased cellularity in tumors or cellular swelling in inflammatory lesions), including MM (Fig. 1) (Ferrari et al., 2014; Herneth et al., 2005). Several studies (Charles-Edwards and deSouza, 2006; Lin et al., 2010; Cafagna et al., 2012; Horger et al., 2011) have already shown that the use of this sequence could improve the conventional MR assessment, particularly for staging different malignancies, including MM in which its use seems to provide interesting results. Narquin et al. (2013) reported that WB-MR/DWIBS is able to detect a higher number of lesions compared with WB-XR, increasing the “Durie/Salmon

Plus stage” in more than one third of the patients. Furthermore, WBMR/DWIBS could assess tumor viability, predict early response to therapy and monitor patients (Horger et al., 2011; Fenchel et al., 2010). However, further clinical studies are still necessary. New PET radiopharmaceuticals have been investigated (Blake et al., 2001; Nanni et al., 2007; Nishizawa et al., 2010) with the aim of overcoming the [18F]FDG limits. In spite of [18F]FDG-PET/CT sensitivity, the uptake can be low in MM lesions and their distinction from benign lesions can be difficult. Each PET radiopharmaceutical allows to evaluate a different metabolic pathway and biological feature. [18F]sodium-fluoride ([18F]NaF) deserves a special mention, in that it is a osteotropic calcium mimetic, non-specific tumor-seeking PET radiopharmaceutical that accumulates in both osteoblastic and osteolytic lesions, thanks to its ability to detect minimal osteoblastic activity accompanying the lytic lesion (Even-Sapir et al., 2007; Sood et al., 2011). An additional advantage is the possibility of revealing minor fractures, difficult to evaluate by conventional imaging (Schirrmeister et al., 2001). [18F]NaF bone uptake is twofold higher and shows faster blood clearance than [99mTc]MDP, resulting in better target-to-background ratio. Moreover, it can benefit of the higher spatial resolution of the PET/CT scanner compared to the gamma camera. Several studies have demonstrated the diagnostic validity of [18F]NaF-PET or PET/CT for the detection of bone metastases (Cook and Fogelman, 2000), but the studies that assessed the value of this tool in the study of MM lesions are still few. In a recent study (Sachpekidis et al., 2014) that compared [18F]NaF and [18F]FDG uptake in skeletal lesions in 60 MM patients, the higher [18F]NaF-PET/CT sensitivity in detecting both osteolytic and osteoblastic lesions was confirmed. Due to the fact that [18F]FDG-PET/CT and [18F]NaF-PET/CT provide different molecular information, the combined use of [18F]NaF and [18F]FDG in a single PET/CT scan has been proposed (Iagaru et al., 2009). This could result of particular importance in MM patients, given that [18F]NaF can precisely localize bone involvement, while [18F]FDG can identify marrow-based disease at an early stage as well as extra-medullary disease. The role of 3 -[18F]fluoro-3 -deoxy-l-thymidine ([18F]FLT) PET/CT in MM patients is also under investigation. [18F]FLT is a DNA precursor designed to evaluate the bone marrow compartment in hematological disorders. [18F]FLT uptake is directly related to the rate of DNA synthesis, depending on the activity of the thymidine kinase-1 enzyme, which is more expressed in tumor cells (during the S-phase of the cell cycle). [18F]FLT-PET provides visual and quantitative information on the entire bone marrow compartment studied. [18F]FLT-PET role in the diagnostic follow-up of MM patients and in distinguishing the different bone marrow disorders has been emphasized by Agool et al. (2006). Other two radiopharmaceuticals tested in MM disease are [11C]Methionine ([11C]MET) and [11C]Choline ([11C]CHO). The first one is a radio-labelled aminoacid that shows higher uptake in plasma cells than in other bone marrow cells, and this results in a good sensitivity in detecting MM-related lesions. The first study dealing with the use of [11C]MET-PET/CT in MM was performed by Dankerl et al. (2007), who demonstrated the ability of [11C]MET-

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PET/CT in estimating tumor burden, detecting active medullary and extra-medullary manifestations, especially in clinically silent situations and/or unexpected localizations. [11C]CHO is a precursor of phospholipids that is involved in membrane metabolism and growth, and its uptake is increased in proliferating cells, in which the mitotic process is faster. Preliminary studies showed that [11C]CHO-PET/CT is more sensitive than [18F]FDG-PET/CT for the detection of MM-related bone involvement (Nishizawa et al., 2010). Differently from the other radiopharmaceuticals described above, [11C]CHO is not excreted with the urine, and this property allows to better evaluate the genito-urinary tract. However, the major drawback of these two radiopharmaceuticals is that they are [11C]-labelled molecules with short half-life of only 20 min. (compared with the longer half-life of [18F]-labelled PET radiopharmaceuticals), which makes them difficult to use in the clinical practice. A new frontier in the field of imaging technology is the introduction of PET/MR scanners, which integrate a MR scanner instead of a CT tomograph. [18F]FDG-PET/CT and WB-MR could theoretically be the best reference diagnostic tools in the diagnosis and follow-up of MM. The integration of these two modalities into one single examination could open a very attractive diagnostic approach. PET/MR instrumentation would provide the best information and would at the same time reduce diagnostic time, long-term costs and the patient exposure to ionizing radiation thanks to the lack of the CT. Unfortunately, PET/MR scanners are expensive and, due to their recent introduction, the diagnostic protocols are still under investigations and its appropriateness must await the results of ongoing clinical researches. A possible inexpensive alternative is the use of softwares based on fusion imaging to integrate two different modalities into one, namely PET/CT and MR, resulting in a postprocessed PET/CT-MR fusion imaging (Antonica et al., 2014). 6. Conclusions Based on the considerations extensively reported above, the following conclusions can be drawn: a) WB-XR is still used in the initial work-up of patients with suspected MM, but it is being more and more replaced by newer and more sensitive imaging techniques. In particular, WB-LDCT is now the imaging procedure of choice at baseline, although WB-MRI should be preferred for the detection of bone marrow infiltration and extra-medullary manifestations; b) none of the imaging techniques currently available are endowed with the clinical and technical requirements necessary for a thorough evaluation of all monoclonal plasma cell disorders; c) multimodality techniques and whole body imaging provide the best advantages to this aim; d) WB-MR and [18F]FDGPET/CT represent the most trustworthy and efficacious imaging modalities for a complete and correct work-up and design of individualized therapies of MM patients; e) [18F]FDG-PET/CT should be preferred in the follow-up of MM patients with persistently high glucose metabolism following first-line therapy, in that it appears to be the only reliable technique able to detect otherwise undetectable skeletal progression; f) integrating these techniques as first-line approach into an updated MM imaging algorithm may improve disease management and the patient’s quality of life. Conflict of interest The authors have declared that no conflict of interest exists. References Agool, A., Schot, B.W., Jager, P.L., Vellenga, E., 2006. 18F-FLT PET in hematologic disorders: a novel technique to analyze the bone marrow compartment. J. Nucl. Med. 47, 1592–1598.

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Biographies Giuseppe Rubini M.D., Ph.D., is specialized in Nuclear Medicine and Radiology. He is Chief of Nuclear Medicine Department in Polyclinic Hospital in Bari, Chief of School of Specialization in Nuclear Medicine and associated professor of Radiology at University of Bari Medical School, Italy. He is member of European Association of Nuclear Medicine (EANM), Associazione Italiana di Medicina Nucle-

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are (AIMN), Società Italiana di Radiologia Medica (SIRM) and he is also advisor for Italy of the International Medical Olympiad in Salonicco. He has published more than 120 manuscripts of national and international journals, being expert in nuclear medicine role in skeletal, oncologic and cardiac diseases. Artor Niccoli Asabella M.D., Ph.D., is specialized in Nuclear Medicine and he has worked as Researcher of University of Bari since 15/04/2005. He is also an official docent of the School of Medicine and Surgery and various courses of Technologist of Medical Radiology and Radiotherapy of the University of Bari, and docent of the Specialization Schools of Nuclear Medicine. He has published over 50 papers published in international peer-reviewed medical journals, in nuclear medicine role in cardiac, neurologic and oncologic diseases. Cristina Ferrari M.D., is concluding her period of specialist training in the School of Specialization in Nuclear Medicine at University of Bari Medical School, Italy. She is a member of Associazione Italiana di Medicina Nucleare (AIMN) and author or co-author of about 20 papers published in international medical journals, with particular scientific interest in the nuclear medicine role in the field of hematologic disorders. Vito Racanelli received his M.D. degree from the University of Bari Medical School, where he also completed a residency in Internal Medicine and obtained his Ph.D. in “Bio-Molecular Diagnostic Research in Internal Medicine and Oncology”. He then moved to the National Institutes of Health (Bethesda, USA) as a visiting scientist in the National Institute of Diabetes & Digestive & Kidney Diseases. After spending three years in the Immunology Section of the Liver Diseases Branch, he returned to Bari to become associate professor of Internal Medicine. He carries out a wide array of basic and applied research for the prevention, diagnosis, and treatment of immune-mediated and lymphoproliferative disorders with results that have been extensively published. Nicola Maggialetti, M.D., is specialist in Radiology and he has worked at in Department of Medicine and Health Sciences at University of Molise since 2013. He is fellow of Computed Tomography Section of Società Italiana di Radiologia Medica (SIRM). He is particularly passionate and expert in MR imaging and his main publications cover this topic. Francesco Dammacco, M.D., is specialist in Internal Medicine and Emeritus Professor of Clinical Medicine at the University of Bari Medical School, Bari, Italy. He has been chief of the Department of Internal Medicine and Clinical Oncology, Polyclinic Hospital in Bari, member of the American Association of Immunologists and of the British Society for Immunology. In addition, he has served a 6-year term as Chairman of the Italian College of Teachers of Internal Medicine. At present, he is Honorary President of the Italian Society of Internal Medicine and of the Italian Society of Immunology, Clinical Immunology and Allergology. As of January 2016, he is author or co-author of 474 papers published in international peer-reviewed medical journals. His main scientific interests include multiple myeloma and related malignancies, cryoglobulinemic vasculitis, autoimmune diseases, immunodeficiency syndromes and amyloidosis.